Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma

Minjie Gao, Hua Bai, Yogesh Jethava, Yujie Wu, Yuqi Zhu, Ye Yang, Jiliang Xia, Huojun Cao, Reinaldo Franqui-Machin, Kalyan Nadiminti, Gregory S. Thomas, Mohamed E. Salama, Peter Altevogt, Gail Bishop, Michael Tomasson, Siegfried Janz, Jumei Shi, Lijuan Chen, Ivana Frech, Guido TricotFenghuang Zhan

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Background: Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant. Methods: Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group. Results: CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P <. 001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P =. 002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo. Conclusion: Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.

Original languageEnglish (US)
Pages (from-to)507-515
Number of pages9
JournalJournal of the National Cancer Institute
Volume112
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gao, M., Bai, H., Jethava, Y., Wu, Y., Zhu, Y., Yang, Y., Xia, J., Cao, H., Franqui-Machin, R., Nadiminti, K., Thomas, G. S., Salama, M. E., Altevogt, P., Bishop, G., Tomasson, M., Janz, S., Shi, J., Chen, L., Frech, I., ... Zhan, F. (2020). Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma. Journal of the National Cancer Institute, 112(5), 507-515. https://doi.org/10.1093/jnci/djz159